Brief Review - Hypertension

Brief Review
Generating Evidence From Computerized
Healthcare Utilization Databases
Giovanni Corrao, Giuseppe Mancia
Preliminary Remarks
Randomized clinical trials (RCTs) are regarded as the highest
level of therapeutic evidence because they are based on random allocation of participants to ≥2 treatment groups, which
provides patients with superimposable initial demographic
and clinical characteristics and allows the results to reflect
the effect of the treatment strategies under study safely. Also,
new treatments are compared with placebo or current interventions, which offers information on their absolute or added
value. Finally, end points of documented clinical relevance are
selected, the results having an immediate bearing for patients’
health.
However, RCTs also have limitations that can make their
results of uncertain and limited application to daily life
medicine.1–4 For example, in RCTs, treatments are delivered
according to preselected plans that make management more
rigid than the one adopted in real-life. Two, treatments are
delivered in a highly controlled environment by operators
with specific competence, which results into a much lower
chance of mistreatment or errors. Three, for several reasons
(cost, progressive patients’ dropout, changes of patient residence, job instability of investigators, etc), RCTs can have a
few year duration only, extrapolation been required to apply
their results to daily life patients with a much longer life
expectancy. Four, to make data scientifically interpretable, in
RCTs, vulnerable patients are usually avoided and patients
are recruited based on restricted eligibility criteria, which do
not reflect the demographic and clinical heterogeneity of the
individuals to whom the trial results are eventually applied.
Finally, in RCTs, high motivation and close follow-up make
patients well compliant to treatment, at variance from clinical
practice in which a low and variable treatment adherence is
common, with unmeasured but probably substantial modifications of the original trial results.5–12
Recognition of the above limitations has favored the design
and conduction of trials, which could may more appropriately
reflect clinical practice. One example is the expansion of the
end points by which to determine the efficacy of the intervention to events (eg, revascularization procedures) diagnostically more open to errors or bias, but nevertheless of a large
prevalence and decision relevance in real life.13 Furthermore,
to ensure a better generalizability of the results, the so-called
pragmatic trials are more and more frequently performed,
with the aim of selecting patients more similar to those in
whom the trial results are applied.14 However, it is widely
thought that this does not substantially reduce the gap between
the artificial environment where trial data are collected and
real-life medicine.15 This has been instrumental in the growth
of interest on observational studies, which could complement
the results of clinical trials with information on how strong
and persistent the effects of healthcare interventions are in
real-life conditions. These studies can make use of 3 different data sources, ie, in-field collected data, disease registries,
and electronically stored databases generated for administrative purposes by health providers or by general practitioners or
specialists. In this review, we will discuss the approach based
on computerized healthcare databases with the aim to highlight their strengths, weaknesses, and potential. We will offer
examples of the importance of the information provided by
these databases on treatment of cardiovascular disease with
particular reference to hypertension and to the large healthcare
database covering since several years the entire citizenship
(10 millions) of the Lombardy region in Italy.
Definition of a Healthcare Database
A healthcare database can be defined as an electronic system
designed to store, on an ongoing basis, disease-related data
(eg, drug prescriptions, hospital diagnoses, outpatient visits,
and so forth) from a well-defined dynamic population, eg, that
covered by a public or private healthcare delivery system or
attended by a network of general practitioners or specialists.
In other terms, disease-related data of interest from a specific
target population need to be available in the definition of a
healthcare database.
Types, Sources, and Characteristics
of Large Healthcare Data
Databases collecting healthcare data can be classified into 2
broad categories: (1) those collecting information for administrative purposes (ie, administrative or healthcare utilization
[HCU] databases) and (2) those generated by medical records
[MRs] to allow physicians to track information on their
patients over time (ie, MR databases).16 A description of HCU
Received November 4, 2014; first decision November 17, 2014; revision accepted December 17, 2014.
From the Division of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods (G.C.); Department of Clinical
Medicine (G.M.), University of Milano-Bicocca, Milan, Italy; and IRCCS, Istituto Auxologico Italiano, Milan, Italy (G.M.).
This article was sent to David A. Calhoun, Guest Editor, for review by expert referees, editorial decision, and final disposition.
Correspondence to Giovanni Corrao, Dipartimento di Statistica e Metodi Quantitativi, Sezione di Biostatistica, Epidemiologia e Sanità Pubblica,
Università degli Studi di Milano-Bicocca, Via Bicocca degli Arcimboldi, 8, Edificio U7, 20126 Milano, Italy. E-mail [email protected]
(Hypertension. 2015;65:490-498. DOI: 10.1161/HYPERTENSIONAHA.114.04858.)
© 2015 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.114.04858
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490
Corrao and Mancia Real-World Data and Clinical Research 491
and MR databases, in comparison with conventional sources
of healthcare information, is provided in Table 1.17–21
HCU databases were initially created to supply payments to
providers of health services within public or private healthcare
delivery systems.22 Their management requires electronically
stored data on patients’ demography, healthcare procedures,
and services representing a cost for Health Authorities, such
as drug dispensations, hospital admissions and diagnoses, surgical and other interventions in and outside hospitals, outpatients visits by general practitioners and specialists, laboratory
examinations, vaccinations, etc. HCU databases are widespread in United States where they are funded by the government (Medicare, Medicaid, and Veteran Administration),
large health insurance companies (eg, United Health), or
health maintenance organizations (eg, Kaiser Permanente).16
More recently, HCU databases have spread to several countries of the European Union, with the advantages, compared
with United States, that data are usually collected from more
stable populations and that health coverage is extended to all
diseases and involves virtually all individuals. Despite these
advantages, HCU databases are not as popular in Europe as
in the United States, mainly because of the difficulty posed by
strict privacy regulations, which has to date favored the use of
MR databases.
The most important MR database is probably the UK General
Practice Research Database, a large computerized database of
anonymized longitudinal patient records from hundred general practitioners and about 3 million patients (ie, ≈5% of the
United Kingdom population).21–23 Similar databases, however,
are available in other European countries. In the Netherlands,
the Integrated Primary Care Information database involves
≈150 general practitioners and up to half a million patients.24
In Italy, the Health Search MR database involves ≈900 general practitioners and >1.2 million patients.25 In Sweden, a
database that includes >75 primary care centers covering an
area with ≈800 000 individuals is used for investigating several fields of healthcare research, including hypertension.26,27
In general, the clinical information provided by MR databases
is much more extensive than that of HCU databases, the data
including lifestyle habits, risk factors, blood pressure values,
and patients’ clinical history. MR databases, however, suffer
from the fact that physicians usually provide information on
patients’ diagnoses and care they are more directly responsible
for, which means that clinical data may not infrequently be
partial and the patient’s overall clinical status unlikely to be
available in a comprehensive database format. Data quality
may also be a problem and selection of participating physicians may be such as to make MR-generated data of uncertain
representativeness of the more general healthcare standard.
Strengths of HCU Databases
HCU databases have important advantages. One, information can be obtained at low cost, over long time frames, and
quickly because data are laid down in an electronic format.
Two, available data include many different healthcare services
(prescription of drug medicaments, medical visits, laboratory
and instrumental examinations, hospitalizations, etc), which
can be electronically linked by an unique patient code so that
for each individual the assigned care, its changes over time,
and its effect on ≥1 outcomes can be tracked. Three, because
of the large size of the covered population (often up to million
patients), data can reliably and timely identify trends in the
use of healthcare interventions, drugs, and devices, which may
allow to verify the consequences of medical recommendations
Table 1. Relative Advantages (+) and Disadvantages (−) of Major Data Sources in Health Research
Prospective Data Collection
Analysis of Existing Databases
Controlled Randomized
Trials
Longitudinal Observational
Studies
Healthcare Utilization
Databases
Less expensive
…
…
+++
+
Promptness of data availability
…
…
+++
+++
Patient awareness/level of intrusion
…
…
+++
+++
Data applicability to multiple conditions/
diseases
…
−
+++
+++
Size of collected data
…
…
+++
++
Patient heterogeneity representativeness
…
++
+++
+
+
Desired Traits for Health Research
Real life clinical practice representativeness
Medical Record Research
Databases
…
+++
+++
Quality/extent of clinical information
+++
++
−
−
Absence of confounding by indication/group
comparability
+++
…
…
…
…
Accessibility by health services investigators
…
…
+
Accuracy of disease coding
+++
+
−
+
Upcoding of diseases or services*
+++
+++
—
+++
Control of collected information by
investigators
+++
+++
…
…
Scandinavian Simvastatin
Survival Study18
The Framingham Heart Study19
Medicaid database20
General Practice Research
Database21
Example
Reprinted from Gandhi et al.17
*Done to maximize reimbursement.
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492 Hypertension March 2015
or changes in healthcare regulations suitably. Four, because
they are recorded independently of patient agreement, data
are immune from the bias related to the selection of patients
by their willingness to participate, an often forgotten limitation impossible to exclude in conventional research studies.28
Finally, and most importantly, HCU databases guarantee that
the information reflects the state of clinical practice in the general population, this being particularly the case where healthcare is assured by a system covering the whole citizenship.
The above advantages are listed in Table 2.
Research Applications of HCU Databases
HCU databases are particularly suitable for investigating the
following areas.
Profiles of Drug Use
HCU data offer accurate information on the prevalence, incidence, and duration of drugs’ use, which is obviously essential
for health system planning and for assessing appropriateness
of prescribing. Drug use measures (including the number of
current users, the new or incident users, and the duration of
use) can be directly obtained and comparisons can be made
between individual drugs or drug classes and between drug
use at different times or in different geographical areas. This
provides a comprehensive picture of the therapeutic habits of
a population and of their temporal modifications.
Of special interest is the possibility offered by HCU data
to study persistence and adherence with chronic therapy,29 ie,
(1) the overall duration of uninterrupted drug therapy often
measured as the cumulative proportion of patients who do
not experience any episode of treatment discontinuation during follow-up (persistence) and (2) the duration of drug use
often measured by the ratio between the cumulative number of
days in which the medication is available and the days of the
overall follow-up (adherence). Because of patients’ unawareness, the HCU data are free from the so-called Hawthorne
effect, namely the behavioral distorsion that occurs when
human beings know to be under observation.30 Furthermore,
the adherence/persistence patterns can be determined over
prolonged follow-ups and their relationship to events can be
assessed by linking the results to those derived from hospitalization or other sources. Using this approach, in the HCU
database from Lombardy, we showed that about one third of
newly treated hypertensive patients discontinued treatment
after the first prescription31 and that only slightly <50% of the
remaining patients did not experience an episode of prolonged
(≥3 months) treatment discontinuation during the follow-up.10
This also occurred for antidiabetic and lipid-lowering drugs,
the rate of prescription coverage being in all instances related
to the rate of hospitalization for cardiovascular morbid
events.31 HCU data have been also shown to help clarifying
the factors related to, and possibly responsible for, treatment
discontinuation. In the Lombardy HCU database, discontinuation of antihypertensive treatment was found to be closely
dependent on the type of drug or treatment strategy (mono or
combination treatment) prescribed.10,32 It was also found to be
majorly affected by patients’ demography, cotreatments, type
and severity of diseases of cardiovascular or noncardiovascular nature, and even adversely influenced by unexpected variables, such as residence in metropolitan areas and density of
the population where the patient lived.33 It should be emphasized that knowledge of the factors involved in low adherence
to treatment is preliminary to and fundamental for any action
that aims at reducing the extent of this phenomenon in real
life. For hypertension, dyslipidemia, and diabetes mellitus,
this would be the most crucial means to improve cardiovascular prevention strategies because for all these diseases nonadherence is majorly responsible for the strikingly low rate
of their therapeutic control. This low control is the primary
reason for the maintenance of cardiovascular disease as the
main cause of death worldwide.34
Postmarketing Studies on Treatment Effectiveness
As pointed out by Cochrane ≈40 years ago,35 RCTs that test
drug efficacy for regulatory purposes aim at assessing the
extent to which an intervention does more good than harm
under ideal circumstances (ie, whether it can work). However,
once its efficacy is established, a medical intervention has to
be and is applied to people and in circumstances that can be
different from the original ones, making the assessment of
its effect in real-world practice (ie, whether it not only can
but also does work crucially important). HCU databases can
provide information on the effectiveness of treatment: (1) in
patients often excluded from premarketing studies or clinical
trials, eg, frail elders, patients with comorbidities, women,
adolescents or younger patients, sometimes with the first demonstration of unanticipated beneficial effects; (2) over times
much longer than those compatible with RCTs or with numbers far greater than those available in in-field observational
studies; and (3) under the low and variable adherence to the
prescribed treatment regimen that is typical of the real-life
population. In this context, HCU data from Lombardy showed
that in the real-world setting, patients who persisted with antihypertensive drug therapy had a 37% reduction in the risk of
Table 2. Major Advantages of Using Healthcare Utilization Databases
Data Characteristics
Advantage
Data are available in electronic format
Low cost of investigation
Data include all healthcare services supplied to
delivery system beneficiaries
A comprehensive healthcare history of each beneficiary
of healthcare system may be available
Patients and doctors are not involved in data collection
Findings are free from bias generated by awareness
of being under observation
Data cover large populations
Outcomes that rarely occur may be investigated
Data collected from unselected populations
Information reflects the state of clinical practice in the general population
(particularly where healthcare is assured to the whole citizenship)
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Corrao and Mancia Real-World Data and Clinical Research 493
coronary events and a 36% reduction in the risk of cerebrovascular events.36 Likewise, good adherence with statins prescriptions was associated with a 19% reduction of the risk of
ischemic heart disease37 and a 25% reduction of the risk of
dementia.38 This shows that the protective effect of antihypertensive and lipid-lowering drugs is not lost when these treatments are implemented in real life, but also that in real life the
degree of protection is highly variable, factors such as adherence to the treatment regimen playing a major role.
Safety Concerns
The longitudinal nature, large size (up to several million individuals), and quick availability make use of HCU databases
extremely attractive also for safety studies, with perhaps an
unsurpassed advantage in the case of treatment-dependent
rare events or long-term effects of drugs and interventions.
The advantage is made even greater by the fact that benefits
and harms of a given medicament or therapeutic strategy can
be assessed on a comparable scale, thereby providing regulatory agencies and caregivers with material for a balanced decision on the net beneficial effect of a therapeutic approach when
applied to the general population.1 An example is offered by the
examination, via the HCU database, of the long-term benefit
and harm of statin administration in the Lombardy population,
the benefit consisting of the reduction of coronary events and
the harm of the reported greater risk of new onset type 2 diabetes mellitus. Over a 6-year follow-up patients with high adherence to the prescribed statin therapy showed an increased risk
of developing diabetes mellitus than patients with low adherence.39 They also showed, however, a clear-cut reduction of the
risk of coronary events,37 the protective effect exceeding the
diabetes mellitus risk, despite its observed greater size (+32%)
than that detected in randomized trials.40 Indeed, the long-term
balance may probably be even more in favor of the beneficial
effect of statins than that calculated in the Lombardy HCU database because in RCTs statins have also been shown to reduce
the risk of stroke.41 Furthermore, as mentioned above, patients
with a high level of adherence to lipid-lowering treatment also
showed a significant reduction in the incidence of dementia,38
a condition associated with a marked increase in the direct and
indirect costs to be covered by health service systems.
the Lombardy population.44,45 From the cost and event incidence data provided by the database itself, it was possible to
conclude that in either case the increase of cost associated with
an increased adherence was, at any adherence level, largely outweighed by the saving inherent to the event reduction, supporting the need for health authorities to engage into an effective
adherence implementation policy. Methodological improvements of the model are desirable to raise the potentiality of
HCU data in this direction and thus make them the basis for
more and more evidence-based healthcare providers’ decisions.
Linkage With Other Databases
HCU databases can be linked with MR data or primary care
center databases (as done by the Swedish Board of Health and
Welfare26,27), as well as with other cohorts that are more rich in
clinical information. This helps reducing the main limitations
(small amount of clinical data, see below), while providing
these other databases with the chance of longitudinal followup on outcomes they would otherwise be deprived of.46
Limitations of HCU Databases and Their
Possible Correction
The Figure shows that interpretation of HCU databases need
to consider several sources of bias. Three main possible biases
are discussed in detail below.
Prescription Versus Consumption
The validity of studies performed with HCU data is based
on the assumption that drug prescriptions correspond to drug
consumption. There is, however, no guarantee that this is
always the case, and indeed it is likely that in many patients
the prescribed drugs are not consumed. This implies, however,
that in the real world, discontinuation of and adherence to
treatment may be even worse than the quantification obtained
via the HCU databases. In other words, that the HCU data,
disappointing as they appear, may only err for optimism, the
possibility that they provide an erroneously unfavorable view
of the real-life situation being highly unlikely.
It should also be mentioned that this type of bias, ie, that an
unknown fraction of patients to whom the drug of interest is
Cost–Effectiveness
Cost–effectiveness analyses are a major challenge for cardiovascular disease, particularly when applied to conditions such
as hypertension, dyslipidemias, and diabetes mellitus in which
both the risk of events and the need of treatment are spread over
the lifetime. It is also an analysis of key importance for healthcare decisions because, for a given level of benefit, resource
allocation to the less costly alternative is necessary,42 especially
at times of financial crises. This is also an area on which HCU
databases may offer an important contribution because (1) calculation of benefit can be based on a real-life long-term event
incidence and (2) direct costs can comprehensively include all
or most healthcare items (drugs, medical visits, hospitalizations, etc), also based on a real life.43 An example of the results
that can be obtained is offered by the calculation of the cost–
effectiveness of healthcare strategies that would increase the
adherence to antihypertensive or lipid-lowering treatments in
Figure. Observational studies based on Healthcare Utilization
Databases, investigating the relationship between therapeutic
regimen and outcome that are affected by 3 sources
of uncertainty, ie, exposure misclassification, outcome
misclassification, and confounding.
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494 Hypertension March 2015
prescribed does not consume the drug, means the introduction
in the database of false-positive drug users. If the medication
does not affect the outcome of interest, this does not produce
any distorsion of the results. On the contrary, if the drug has an
effect, this type of bias tends to mask (namely to drag toward
the null) the estimated drug–outcome association.
Table 3. Sensitivity and Specificity of Diagnoses Made at
Discharge From Hospital or Outpatient Care
Hypertension
60.6
87.7
65
99.9
Other Types of Drug Exposure Misclassification
COPD
53.4
87.9
91
98.8
Drug prescription data may be misclassified because prescription
is incomplete, its reading is erroneous or mistakes in drug coding
are made. However, when filling drug prescriptions, pharmacists
have little room for interpretation and reimbursement by Health
Authorities are made on the basis of detailed, complete, and
accurate claims that are submitted electronically.47–49 Pharmacy
dispensing information is, therefore, expected to provide highly
accurate data, also because filling an incorrect report about dispensed drugs has legal consequences.50
In spite of these reassuring considerations, in several databases, incompleteness of information may generate exposure
misclassification. Incompleteness often consists of missing data
on (1) free sample drugs, (2) nonreimbursed over-the-counter
medications,51 (3) drugs dispensed during hospitalizations,52
and (4) calculations of days covered by a given dispensation.
For instance, when comparing 2 antihypertensive medications,
if 1 of the 2 is (1) more often delivered by the pharmacist overthe-counter (eg, because of its lower cost), (2) dispensed also in
the hospital setting, or (3) prescribed at a higher than the defined
dose (eg, because this is indicated for more severe patients),
a misclassification is generated, more person-time being classified as unexposed when it is in fact exposed (or vice versa)
in one than the other comparison group. Thus, some forms of
approximation are unavoidable for most HCU-based studies.53,54
The effect of these approximations on the validity of the results
will have to be always explored by sensitivity analyses (ie, by
evaluating the robustness of the findings through modifications
of the approximation criteria).55,56
Outcome Misclassification
To generate reliable data, a HCU database must guarantee that
the selected outcome is assessed with sufficient sensitivity and
specificity. For example, if the database misses a noticeable
fraction of patients experiencing an acute myocardial infarction or a stroke, sensitivity is limited, whereas if the database
erroneously attributes to a myocardial infarction or a stroke,
a noticeable number of hospitalizations is generated by other
diseases, the limitation involves specificity. It is important to
mention that for proper assessment of the relationship of a
given treatment with outcome, a limited specificity is more
damaging than a limited sensitivity, a 100% specificity of the
outcome assessment allowing an unbiased estimate of the
measured association, irrespective of the sensitivity value.57
It should also be mentioned that, based on the available literature, in HCU data diagnostic misclassifications is not as common as it might at first sight appear.58 A recent comprehensive
study has shown that in the HCU databases, sensitivity was
only small or moderate, whereas specificity was usually ≥95%
(Table 3).58,59 In general, a high specificity may be expected
when diagnoses are based on hospital records, whereas performance is likely to be worse when diagnoses are based on
Outpatient Care Billing
Diagnoses
Disease
Hospital Discharge
Diagnoses
Sensitivity Specificity Sensitivity Specificity
Diabetes mellitus
62.6
97.2
88
99.4
Renal failure
18.6
99.0
88
99.4
Chronic liver disease
27.6
99.8
100
100
Any cancer
44.8
95.0
91
100
100
Peptic ulcer disease
27.6
94.6
92
Congestive heart failure
41.5
96.1
85
99
Acute myocardial infarction
25.4
96.8
94
100
Neutropenia
…
…
…
97
Stevens–Johnson syndrome
…
…
…
95
Reprinted from Schneeweiss and Avorn.58 COPD indicates chronic obstructive
pulmonary disease.
out-of-hospital identification of diseases (eg, by general practitioners or specialists).
Despite these considerations, diagnostic validation is usually recommended not only for out-of-hospital but also for
hospital-derived data. This may make use of findings from
published validation studies performed in other populations
although some60 thought that validation data generated from
the in-study database are always required. In this context,
however, a major difficulty is represented by the privacy regulations that in several countries prevent individual MRs from
being thoroughly reviewed. Thus, diagnostic validation via
sensitivity analyses that verify the robustness of the findings
by applying credible sensitivity and specificity ranges to the
source of diagnostic information is often the only practical
option.
Another potential limitation of HCU database is that
certain diseases cannot be reliably identified from hospital
records because they rarely lead to hospitalization. However,
the issue can be approached by identifying the addition of
their therapeutic drugs to the medical prescription, provided
that the drugs are only used for the disease under study. A
pertinent example is the effect of statins on the onset of type 2
diabetes mellitus because (1) except perhaps in its late stage,
only occasionally diabetes mellitus is the cause of hospital
admission and (2) antidiabetic drugs are not used for any
other disease. The use of antidiabetic medications as a proxy
for diabetes mellitus onset has allowed to make interesting
observations on the influence of cardiovascular treatments on
the development of diabetes mellitus in the general population.39,61 It should be emphasized, however, that this approach
is likely to have a low sensitivity because in several cases
appearance of the disease may not be associated with specific
treatment initiation. Specificity, on the other hand, may be
optimized by using strict criteria for the disease identification (eg, by diagnosing new onset diabetes mellitus only in
patients with several consecutive prescriptions of antidiabetic
drugs. This strengthens the above-mentioned need, for the
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Corrao and Mancia Real-World Data and Clinical Research 495
HCU database approach, to always check the validity of the
results by sensitivity analysis.
Confounding
There is no question that the most important concern against
HCU databases is confounding. This is particularly the case
for that common and often insidious and uncorrectable form
of confounding, endemic to pharmacoepidemiology and
healthcare research studies, that is known as confounding by
indication. Namely, the observation that a given medication
is associated with an increased likelihood of outcome onset
for which is thought to be responsible while the explanation
lies in its greater use in patients more prone to develop the
outcome.
Strategies to adjust for such a bias vary depending on the
amount of information included in the database. If all or most
factors representing potential confounders are available, propensity-score methods simultaneously accounting for a large
number of patient characteristics can be used with an effective
reduction of confounding biases.62 However, because HCU
databases generally have a limited amount of clinical information, methods accounting for unmeasured confounders should
be adopted to avoid or at least limit the effect of bias. One
such method, called user-only design, is to restrict the cohort
analysis to patients under the in-study medicaments, thereby
comparing only individuals in which the need to use them was
initially established.63
Other methods aim at ensuring a better comparability of
different therapeutic strategies by other types of restriction of
the original cohort. In this respect, a pivotal study of statin
treatment and 1-year mortality showed a reduced influence of
confounding by using progressively stricter criteria for cohort
inclusion.64 Starting from a mortality reduction of 68% among
the entire cohort of statin users, the restriction of the cohort
to incident users only,65 the selection of a comparison group
similar to the intervention group and the exclusion of patients
with contraindications and low adherence to treatment led to
a final estimate of a 28% reduction, a figure similar to that
obtained from the pooled estimate by RCTs.64 In general, it is
thought that a set of 3 restrictions can be adopted in comparative effectiveness research with no major impairment of data
generalizability.28
Restricting the investigated cohort only to patients who
experience the in-study outcome (case-only design) is another
possibility, its use in pharmacoepidemiology and healthcare
research via methods such as the case-crossover66 and the
self-controlled case series design67 being regarded as attractive (particularly in patients with transient exposure to or acute
outcomes from drug use) because of the ability to evaluate
time-invariant confounders. For antihypertensive therapy, an
example has recently been provided by a study that compared
the risk of discontinuing antihypertensive therapy in patients
under generic versus brand-name drugs.68 Given the possibility that physicians would prescribe one or the other drug
type according to the severity of clinical profile, only patients
discontinuing treatment who experienced both generic and
brand-name drug exposures during a suitable follow-up were
analyzed. The results showed that treatment discontinuation
did not differ in the 2 conditions, a conclusion drawn by a
within-patient comparison that could be reasonably assumed
to be exempted from the above-mentioned possible between
patient imbalance.
Finally, new analytic techniques, such as sensitivity analysis,69 instrumental variable methods,70 or propensity score
calibration,71 are increasingly applied to HCU databases to
account for residual confounding. Although a description
of their rationale and functioning is beyond the scope of the
present review, an example of the advantages of the use of
these methods may help the reader to penetrate this complex
area. In a study on the Lombardy HCU database, it has been
observed that, compared with hypertensive patients starting
treatment with a fixed-dose combination of 2 antihypertensive
drugs, those on a free or liberal combination exhibited a 15%
significant increase in the risk of coronary or cerebrovascular
morbid events.72 Although considering a medical explanation
of this finding, the possibility of its origin from confounding
(ie, a more frequent use of free combinations in patients with
more severe hypertension or a worse cardiovascular risk profile in the belief that giving drugs separately makes titration to
full effect easier and blood pressure reduction more balanced)
prevented any reliable interpretation of the results. By omitting sources of selective prescribing (eg, because these data
are not available from the HCU database used for investigating
this issue) biased estimates of the drug–outcome association
are systematically generated. However, biased estimates may
be externally adjusted if information on physicians’ prescriptive behavior and on the strength of the confounder–outcome
association (ie, to what extent patients’ clinical characteristics affect prescribing and cardiovascular risk, respectively)
is available. Information on physician’s prescriptive behavior
may be obtained from MR data on a sample of the population
covered from the HCU database, whereas data on the confounder–outcome association may be derived from epidemiological or intervention studies (hopefully in the same or in a
similar population), the 2 sets of data combined being used to
estimate the bias factor (ie, the residual bias that would result
from failure to check for these confounders). In addition, a
Monte Carlo sampling procedure may be used to deal with
the random uncertainty of externally adjusted estimates,73
the results being tested against an unmeasured confounder,
selected among those known to be common in the population
at study and to have a substantial effect on the outcome of
interest. In the above-mentioned case, the use of the abovementioned corrections abolished the increased cardiovascular
risk seen in patients starting treatment with a free compared
with a fixed-dose drug combination (odds ratio, 1.00; 95%
confidence interval, 0.89–1.12).
Challenges and Concluding Recommendations
HCU databases are attractive because they provide huge
amounts of data. Their representativeness of the population
under investigation and capacity to offer longitudinal type of
information for extended follow-ups at individual patient level
make this approach useful for clinical observational research,
especially on drug use and outcomes. Its application also
includes studies of physician prescribing and patient compliance, as well as those focusing on safety, effectiveness, and
cost–effectiveness of therapeutic strategies. HCU data cannot
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496 Hypertension March 2015
substitute RCTs but they may fill in gaps where RCTs will
probably not be done and generate real-life–based hypotheses
to be tested by RCTs.
However, quantity has little merit in the absence of a sufficient
level of quality, and as far as HCU databases are concerned several examples have been given that debatable eligibility criteria, incompleteness or incorrectness of linkage variables, errors
in quantification of care exposure, inaccurate identification of
outcome and, above all, confounding resulted into incorrect
conclusions.74,75 This may produce damage because HCU databases offer great opportunities but they also carry, as it has been
emphasized in a recent editorial,76 the responsibility that their
conclusion may lead to decisions that involve the health care
of a large number of beneficiaries. Proper use of HCU databases need not forget challenges that are still inherent to this
approach. Although technical progress allows in most instances
to collect, store, and disclose quickly to analysis even huge
and rapidly growing amounts of data, some concern remains
on privacy and security regulations. Furthermore, completeness
and quality of data continue to remain an issue for some HCU
databases, the great disparity between data included in different databases (because they are usually collected under different jurisdictions for financial rather than for clinical or research
purposes),77 representing a barrier to their pooling and comparisons between different regions or countries. Finally, if data
are analyzed uncritically, ie, without consideration for possible
misclassification and confounding, skepticism is generated and
the credibility of the approach is undermined. Fortunately, data
collection and analysis have undergone substantial progress in
the past decade,15,58,78–80 so that poor quality or incomplete databases cannot anymore be justified on technical grounds. Further
important improvements are expected in the near future because
preservation of privacy and security are being addressed by
new authentication approaches and policies that better safeguard patient-identifiable data. Furthermore, reimbursement
policies are making more and more use of automatic devices
(eg, individual magnetic card) that will automatically generate
data virtually free from errors or omissions. All these justify the
opinion of the authors of this review that HCU data will be more
and more recognized to be a powerful tool in the research area
in which they belong, as long as they are (1) used with appropriate attention to their potential limits, (2) based on transparent
protocols81 and recognized quality standards,82 and (3) analyzed
by proper statistical methods that allow the pitfalls inherent to
this approach to be at least, in part, corrected.
Disclosures
G. Corrao received research support from the European Community
and the Italian Agency of Drug, and the Italian Minister for
University and Research. He took part to a variety of projects that
are funded by the pharmaceutical industry (Novartis and GSK). He
also received honoraria as member of Advisory Board from Roche.
G. Mancia received honoraria as lecturer and chairman in Meeting or
Advisory Boards from Bayer, Boehringer Ingelheim, Daiichi Sankyo,
Medtronic, Menarini, Novartis, Recordati, Servier, and Takeda
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Generating Evidence From Computerized Healthcare Utilization Databases
Giovanni Corrao and Giuseppe Mancia
Hypertension. 2015;65:490-498; originally published online January 26, 2015;
doi: 10.1161/HYPERTENSIONAHA.114.04858
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